Process for preparing 1, 4-androstadiene-2, 17beta-diol-3-one



United States Patent 9 3,081,317 PROCESS FOR PREPARiNG1,4-ANDROSTADIENE- 2,17,8-DIOL-3- NE Robert L. Clarke, Bethlehem, N.Y.,assignor to Sterling vDrug Inc.,New York, N.Y., a corporation ofDelaware No Drawing. Filed Mar. 16, 1959, Ser. No. 799,459

1 6 Claims. (Cl. 260--397.4)

This invention relates to .a novel steroid compound,,1,j4randrostadiene-2,l7fi-diol-3-one, to others and esters thereof, andto a process for the preparation thereof.

3,081,317 Patented Mar. 12, 1963 as dimethyl sulfate or methyl iodide inthe presence of ia .;The compounds of the invention are .of thefollowing general formula O R OH:

wherein R represents hydrogen or a lower-alkyl or car- .boxylic acylradical, and R represents hydrogen'or a ing from one to about fourcarbon atoms, thus including such radicals as methyl, ethyl,propyl,.isopropy1, butyl, secondary-butyl, isobutyl, and the like.

In the above general Formula I whenR and/or R represent carboxylic acylradicals, they stand for acyl radicals derived from carboxylic acidshaving from one to about ten-carbon atoms, conventionally employed inthe steroid art, and having a molecular weight less than about 250.Representative of the acyl radicals which can .be present areloWer-alkanoyl radicals, e.g., formyl, acetyl,

propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl,trimethylacetyl, and the like; carboxy-loweralkanoyl radicals, e.g.,succinyl (,B-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals,e.g., d-cyciopentylpropionyl, fi-cyclohexylpropionyl, and the like;monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, pnitrobenzoyi,3,4,5 trimethoxybenzoyl, and the like; monocarbocyclicaryl-lower-alltanoyl or -alkenoyl radicals, such as phenylacetyl,S-plrenylpropionyl, cinnamoyl, and the like; and monocarbocyclicaryloxy-lower-alkanoyl radicals, such as p-chlorophenoxyacetyl, and thelike.

According to the proces of my invention,1,4-androstadiene-Z,l7;3-diol-3one is prepared by treating4-androstone-25,1'713-diol-3-0ne or a monoor dicarboxylic ester thereofwith oxygen under aqueousalkaline conditions.

A water-miscible, organic solvent, for example, a loweralkanol, ispreferably present in the reaction mixture to cause at least partialsolution of the steroid. If the starting material is esterified, theester groups are hydrolyzed during the reaction. The reaction takesplace readily at room temperature.

The compounds of- Formula I'wherein R and/or R represent carboxylic acylradicals are prepared by conventional esterification reactions, forexample, by reacting the free steroid alcohol with the appropriate acidanhydride or acid halide in the presence of an organic base such aspyridine. Half esters can be obtained by regulatin; the proportions ofreactants and the reaction condi- The compounds of Formula I wherein Ris a lowerallzyl radical are prepared by conventional etherificationreactions, for example, by reacting the diol or a 17-acylate strongbase. The free hydroxy group at position 17 is not etherified underthese conditions.

.The compounds of the invention are useful-asintermediates for compoundshaving an aromatic. ring A characteristic of the estrogens. Thetransformation is effected by the dienone-phenol rearrangement reactionfirst discovered by Inhoffen and coworkers. This involves ruigration ofthe angular methyl group at C to either the 2- or the l-position,followed by aromatization of the A-ring (cf. Fieser and Fieser, NaturalProducts Related to .Phenanthrene, Reinhold Publishing Corp. 1949, page33-6). .The compounds of the inventionhave also been found to possessanabolic activity while lacking androgenic activity.

The following examples will further illustrate vtheinvcn- .tion withoutthe latter being limited-thereby.

EXAMPLE 1 1,4-andr0smdiene-2J7fl-di0l-3-0ne (I;'R and R are H).--To apartial solution of 6.0 g. (0.0155 mole) of pulverized2,8,l7,8-diacetoxy-4-androsten-3-one, M.P. 199- 201" C., in 250 ml. ofethanol was added a solution of 4.0 g. of potassium hydroxide (85%purity) in ml. of water. The mixture was stirred vigorously at roomtemperature while a stream of oxygen gas was bubbled through it. Withinthirty minutes all of the solid ha'd dissolved. The stirring was stoppedbut the gas addition was continued for a total of seven hours. Aceticacid (5 ml.) was then added and the colorless solution was concentratedto a 225 ml. volume by warming in vacuo. Theprecipitated solid wascollected by filtration-from the cooled mixture, air dried, andrecrystallized from ethyl acetate to give 3.3 g. ofl,4-androstadiene-2,l7B-diol-3-0ne in the form of'colorless rods andprisms, M.P. 207-209 C., [a] -I6.Z (1% in choloroform); ultravioletmaximum at 254 mu.

Analysis.Calcd. for O l-[ 0 C, 75.46; H, 8.67.

Found: C, 75.72; H, 8.90.

The same product canbe obtained'by replacing the2B,17fi-diacetoxy-4-androste. -3-one in the above example by a molarequivalent amount of 4-androstene-2fi,l7fldiol-3-one.

EXAMPLE 2 in an ether-methylene di-chloride-pentane (1:128) mixture andchromatographed on 300 g. of silica gel. Gradual change of the solventmixture to a 4:1:5 ratio eluted the desired diacetate which, after asingle recrystallization from methanol, amounted to 2.25 g. of2,17B-diacetoxy-1,4-and1"ostadien-3 -one, M.P. 208.5209.5 C., [a] =+12.6(1% in chloroform); ultraviolet maximum at 248 m (E=16,600).

Analysia-Calcd. for C I-1 0 C, 71.10; H, 8.30; O, 20.59. Found: C,71.30; H, 8.22, O, 20.60.

By replacement of the acetic anhydride in the preceding preparation byamolar equivalent amount of propionic anhydride, caproyl chloride,succinic anhydride, /3-cyclopentylpropionyl chloride, benzoyl chloride,p-nitrobenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, phenylacetylchloride, or cirinarnoyl chloride, there can be obtained, respectively,2,17,8-dipropionoxy-l,4-androstadiem3 one, 2,17,B-dicaproyloxy-1,4-androstadien-3-one, 2,17 3 -'bis (B-carboxypropionoxy)-1,4-androstadien-3-one,2,17[3-bis(pcyclopentylpropionoxy) 1,4 androstadien-3-one, 2,175-dibenzoyloxy-1,4-androstadien-3-one, 2, l7,B-bis (p nitrobenzoyloxy)1,4-androstadien-3-one, 2,l7,B-bis(3,4,5-trimethoxybenzoyloxy) 1,4androstadien 3 one, 2,1718- bis(pheny-lacetoxy)-1,4 androstadien 3 one,or 2,175- dicinnamoyloxy-1,4-androstadien-3-one.

EXAMPLE 3 Z-methoxy-I,4-andrsmdien-17fi-ol-3-0ne (I; R is CH R is H).Toa solution of 3.04 g. (0.01 mole) of 1,4- androstadiene-Z,l7B-diol-3-one(Example 1), M.P. 202- 208 C., in 90 ml. of absolute ethanol and 10 ml.of 2 N sodium hydroxide solution was added a solution of 1.89 g. (0.015mole) of dimethyl sulfate in 10 ml. of absolute ethanol. After theresulting solution had stood at room temperature for three hours, thesolvent was removed by warming in vacuo, and the residue Was stirredwith Water and ether. The layers were separated, the water layer wasextracted with ether, and the combined ether layers concentrated todryness. The residue was chromatographed on 100 g. of activatedmagnesium silicate starting with a solvent mixture ofether-pentane-methylene dichloride (212:1). Gradual change to a 4:1ethermethylene dichloride mixture eluted the initial portions of thedesired product. The remainder of the product was eluted with a 4:1ether-acetone mixture. A single recrystallization of the total productfrom acetone gave 1.06 g. of Z-methoxy-1,4-androstadien-17/3-ol-3-one inthe form of colorless, massive prisms, M.P. 215218.5 C.

By replacement of the dimethyl sulfate in the preceding preparation by amolar equivalent amount of diethyl sulfate, propyl iodide, isopropyliodide, or dibutyl sulfate, there can be obtained, respectively,2-ethoxy-l,4-androstadien-17fi-ol-3-one, 2-propoxy-1,4-androstadien-17Bol- 3-one, 2-isopropoxy-1,4-androstadien-17,8-01-3-one, or 2-butoxy-1,4-androstadien-17fi-ol-3-one.

Z-methoxy-1,4-androstadien-17fl-ol 3-one can be caused to react withacetic anhydride in pyridine according to the manipulative proceduredescribed above in Example 2 to giveZ-methoxy-17/3-acetoxy-1,4-androstadien-3-one.

I claim:

1. The process for preparing 1,4-androstadiene-2,17 3- diol-3-one whichcomprises treating with oxygen under aqueous alkaline conditions acompound selected from the group consisting of4-androstene-2B,17/3-diol-3-one and carboxylic acid esters thereof.

2. The process for preparing 1,4-androstadiene-2,17/3- diol-3-one whichcomprises treating with oxygen under aqueous alkaline conditionsZfi,17,8-diacetoxy-4-androsten- 3-one.

3. The process for preparing an ester of1,4-androstadiene-Z,17B-diol-3-one which comprises treating with oxygenunder aqueous alkaline conditions a compound selected from the groupconsisting of 4-androstene-2,8,17B- diol-3-one and carboxylic acidesters thereof, and reacting the resulting l,4androstadiene-2,17/3-diol3 one with a member of the group consisting of carboxylic acidanhydrides and carboxylic acid halides in the presence of an organicbase.

4. The process for preparing 2,17;8-diacetoxy-1,4-androstadien-3-onewhich comprises treating with oxygen under aqueous alkaline conditions2,8,17p-diacetoxy-4- androsten-3-one, and reacting the resulting1,4-androstadiene-2,l7B-diol-3-one with acetic anhydride in the presenceof an organic base.

5. The process for preparing a 2-lower-alky1 ether of1,4-androstadiene-2;'17,8 diol-3-one which comprises treating withoxygen under aqueous alkaline conditions a compound selected from thegroup consisting of 4-androstene- 25,17B-diol-3-one and carboxylic acidesters thereof, and reacting the resulting1,4-androstadiene-2,17/8-diol-3-one with a lower-alkyl ester of a strongacid in the presence of a strong base.

6. The process for preparing 2-methoxy-1,4-androstadien-17fi-ol-3-onewhich comprises treating with oxygen under aqueous alkaline conditions2,8,17fl-diacetoxy-4- androsten-3-one, and reacting the resulting1,4-androstadiene-2,17p-diol-3-one with dimethyl sulfate in the presenceof a strong base.

References Cited in the file of this patent UNITED STATES PATENTS2,948,740 Baran Aug. 9, 1960 OTHER REFERENCES Baran: J. Am. Chem. Soc.,vol. 80, pages 1687-91 (1958).

1. THE PROCESS FOR PREPARING 1,4-ANDROSTADIENE-2,17$DIOL-3-ONE WHICHCOMPRISES TREATING WITH OXYGEN UNDER AQUEOUS ALKALINE CONDITIONS ACOMPOUND SELECTED FROM THE GROUP CONSISTING OF4-ANDROSTENE-2B,17B-DIOL-3-ONE AND CARBOXYLIC ACID ESTERS THEREOF.